tbuckley/cabot-search huggingface dataset:
The impact of rare protein coding genetic variation on adult cognitive function
Authors: Chia-Yen Chen, Ruoyu Tian, Tian Ge, Max Lam, Gabriela Sanchez-Andrade, Tarjinder Singh, Lea Urpa, Jimmy Z. Liu, Mark Sanderson, Christine Rowley, Holly Ironfield, Terry Fang, Aija Kyttälä, Amanda Elliott, Anders Kämpe, Andre Sourander, Annamari Tuulio-Henriksson, Anssi Solismaa, Antti Tanskanen, Ari Ahola-Olli, Arto Mustonen, Arttu Honkasalo, Asko Wegelius, Atiqul Mazumder, Auli Toivola, Benjamin Neale, Elina Hietala, Elmo Saarentaus, Erik Cederlöf, Erkki Isometsä, Heidi Taipale, Imre Västrik, Jaana Suvisaari, Jari Tiihonen, Jarmo Hietala, Johan Ahti, Jonne Lintunen, Jouko Lönnqvist, Juha Veijola, Julia Moghadampour, Jussi Niemi-Pynttäri, Kaisla Lahdensuo, Katja Häkkinen, Katriina Hakakari, Kimmo Suokas, Marjo Taivalantti, Markku Lähteenvuo, Martta Kerkelä, Minna Holm, Nina Lindberg, Noora Ristiluoma, Olli Kampman, Olli Pietiläinen, Risto Kajanne, Sari Lång-Tonteri, Solja Niemelä, Steven E. Hyman, Susanna Rask, Teemu Männynsalo, Tiina Paunio, Tuomas Jukuri, Tuomo Kiiskinen, Tuula Kieseppä, Ville Mäkipelto, Willehard Haaki, Zuzanna Misiewicz, Mitja I. Kurki, Jarmo Körkkö, Jukka Moilanen, Outi Kuismin, Mark Daly, Aarno Palotie, Ellen A. Tsai, Hailiang Huang, Matthew E. Hurles, Sebastian S. Gerety, Todd Lencz, Heiko Runz
Journal: Nature Genetics (2023)

Abstract Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population ( n = 485,930). We identify eight genes ( ADGRB2 , KDM5B , GIGYF1 , ANKRD12 , SLC8A1 , RC3H2 , CACNA1A and BCAS3 ) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.
Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial
Authors: Sarah A. Hosgood, Christopher J. Callaghan, Colin H. Wilson, Laura Smith, Joanne Mullings, Jennifer Mehew, Gabriel C. Oniscu, Benedict L. Phillips, Lucy Bates, Michael L. Nicholson
Journal: Nature Medicine (2023)

Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .
“I thought I would be safe in hospital, but I wasn’t”
Authors: Adele Waters, Ingrid Torjesen
Journal: BMJ (2023)

Jade, who has multiple chronic health problems which require hospital admission, shares her story as part of <i>The BMJ</i> and <i>Guardian</i>’s investigation into sexual assault in the NHS. She has launched a claim against Derriford Hospital in light of the sexual assault she experienced there
BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance
Authors: Xiaodong Shu, Jianjie Li, Un In Chan, Sek Man Su, Changxiang Shi, Xin Zhang, Tingting An, Jun Xu, Lihua Mo, Jianlin Liu, Yuqing Wang, Xiaoling Li, Min Deng, Josh Haipeng Lei, Chunfei Wang, Hao Tian, Sun Heng, Joong Sup Shim, Xuanjun Zhang, Yunlu Dai, Zhicheng Yao, Xiaying Kuang, Ying Lin, Chu-Xia Deng, Xiaoling Xu
Journal: Cancer Research (2023)

Abstract Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFβ–ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA. Significance: BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.
The promise of AI and technology to improve quality of life and care for older adults
Authors: Peter M. Abadir, Rama Chellappa, Niteesh Choudhry, George Demiris, Deepak Ganesan, Jason Karlawish, Rose M. Li, Jason H. Moore, Jeremy D. Walston, Benjamin Marlin, Najim Dehak, Alicia I. Arbaje, Mathias Unberath, Thomas K. M. Cudjoe, Suchi Saria, Esther Oh, Nancy Lundebjerg, Christopher G. Chute, Phillip Phan, Quincy Samus, Nancy L. Schoenborn
Journal: Nature Aging (2023)
Which trial do we need? Plasma metagenomic next-generation sequencing to diagnose infections in patients with haematological malignancies and febrile neutropenia: proposal for a randomized-controlled trial
Authors: Catherine A. Hogan, Steve Miller, Anne Piantadosi, David C. Gaston, Patricia J. Simner, Stephen Nash, N. Esther Babady
Journal: Clinical Microbiology and Infection (2023)
Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial
Authors: Julie Mankikian, Agnès Caille, Martine Reynaud-Gaubert, Marie-Sara Agier, Julien Bermudez, Philippe Bonniaud, Raphael Borie, Pierre-Yves Brillet, Jacques Cadranel, Isabelle Court-Fortune, Bruno Crestani, Marie-Pierre Debray, Emmanuel Gomez, Anne Gondouin, Sandrine Hirschi-Santelmo, Dominique Israel-Biet, Stéphane Jouneau, Karine Juvin, Julie Leger, Mallorie Kerjouan, Charles-Hugo Marquette, Jean-Marc Naccache, Hilario Nunes, Laurent Plantier, Grégoire Prevot, Sébastien Quetant, Julie Traclet, Victor Valentin, Yurdagul Uzunhan, Lidwine Wémeau-Stervinou, Theodora Bejan-Angoulvant, Vincent Cottin, Sylvain Marchand-Adam
Journal: European Respiratory Journal (2023)

Background Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. Methods In a randomised, double-blind, two-parallel group, placebo-controlled trial ( NCT02990286 ), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. Findings Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 ( se 1.13) in the rituximab+MMF group and −2.01 ( se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41–6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23–0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. Interpretation Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.
Drivers determining tuberculosis disease screening yield in four European screening programmes: a comparative analysis
Authors: Dominik Zenner, Daniella Brals, Joanna Nederby-Öhd, Dee Menezes, Robert Aldridge, Sarah R. Anderson, Gerard de Vries, Connie Erkens, Valentina Marchese, Alberto Matteelli, Morris Muzyamba, Job van Rest, Ineke Spruijt, John Were, Giovanni Battista Migliori, Knut Lönnroth, Frank Cobelens, Ibrahim Abubakar
Journal: European Respiratory Journal (2023)

The World Health Organization End TB Strategy emphasises screening for early diagnosis of tuberculosis (TB) in high-risk groups, including migrants. We analysed key drivers of TB yield differences in four large migrant TB screening programmes to inform TB control planning and feasibility of a European approach.We pooled individual TB screening episode data from Italy, the Netherlands, Sweden and the UK, and analysed predictors and interactions for TB case yield using multivariable logistic regression models.Between 2005 and 2018 in 2 302 260 screening episodes among 2 107 016 migrants to four countries, the programmes identified 1658 TB cases (yield 72.0 (95% CI 68.6-75.6) per 100 000). In logistic regression analysis, we found associations between TB screening yield and age (≥55 years: OR 2.91 (95% CI 2.24-3.78)), being an asylum seeker (OR 3.19 (95% CI 1.03-9.83)) or on a settlement visa (OR 1.78 (95% CI 1.57-2.01)), close TB contact (OR 12.25 (95% CI 11.73-12.79)) and higher TB incidence in the country of origin. We demonstrated interactions between migrant typology and age, as well as country of origin. For asylum seekers, the elevated TB risk remained similar above country of origin incidence thresholds of 100 per 100 000.Key determinants of TB yield included close contact, increasing age, incidence in country of origin and specific migrant groups, including asylum seekers and refugees. For most migrants such as UK students and workers, TB yield significantly increased with levels of incidence in the country of origin. The high, country of origin-independent TB risk in asylum seekers above a 100 per 100 000 threshold could reflect higher transmission and re-activation risk of migration routes, with implications for selecting populations for TB screening.
Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice
Authors: Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Applewhite, Kathleen Jee, Monika Deshpande, Miguel Flores-Bellver, Ming-Wen Hu, Chuanyu Guo, Shaima Salman, Yousang Hwang, Nicole M Anders, Michelle A Rudek, Jiang Qian, M Valeria Canto-Soler, Gregg L Semenza, Silvia Montaner, Akrit Sodhi
Journal: Journal of Clinical Investigation (2023)

Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by hypoxia-inducible factor (HIF)-1 and -2 (HIFs) remain elevated in diabetic eyes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF-inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
Tropical cyclone and daily respiratory mortality across East Asia: a time series study
Authors: Cheng He, Renjie Chen, Ho Kim, Masahiro Hashizume, Whanhee Lee, Yasushi Honda, Satbyul Estella Kim, Yue Leon Guo, Alexandra Schneider, Wenzhen Ge, Yixiang Zhu, Lu Zhou, Haidong Kan
Journal: European Respiratory Journal (2023)

The threat of tropical cyclones in East Asia is a critical public health issue and a key reason for constructing adaptation strategies for the challenges of climate change. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: All authors have nothing to disclose.
Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality
Authors: Tiffany Shi, Ashley R. Burg, J. Timothy Caldwell, Krishna M. Roskin, Cyd M. Castro-Rojas, P. Chukwunalu Chukwuma, George I. Gray, Sara G. Foote, Jesus A. Alonso, Carla M. Cuda, David A. Allman, James S. Rush, Catherine H. Regnier, Grazyna Wieczorek, Rita R. Alloway, Adele R. Shields, Brian M. Baker, E. Steve Woodle, David A. Hildeman
Journal: Journal of Clinical Investigation (2023)

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.
<i>Notes from the Field:</i> Multistate, Multiserotype Outbreak of <i>Salmonella</i> Infections Linked to Cashew Brie — United States, 2021
Authors: Kailey Lewis, Michael Vasser, Katie Garman, Jeffrey Higa, Michael Needham, D. J. Irving, Steffany Cavallo, Dominique Sullivan, None Marks, Margaret Kirchner, Asma Madad, Zachary D. McCormic, John Dunn
Journal: MMWR Morbidity and Mortality Weekly Report (2023)
Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity
Authors: Xiuting Liu, Graham D. Hogg, Chong Zuo, Nicholas C. Borcherding, John M. Baer, Varintra E. Lander, Liang-I Kang, Brett L. Knolhoff, Faiz Ahmad, Robin E. Osterhout, Anna V. Galkin, Jean-Marie Bruey, Laura L. Carter, Cedric Mpoy, Kiran R. Vij, Ryan C. Fields, Julie K. Schwarz, Haeseong Park, Vineet Gupta, David G. DeNardo
Journal: Cancer Cell (2023)
<i>QuickStats</i>: Age-Adjusted Percentage* of Adults Aged ≥18 Years Who Take Prescription Medication for Depression,† by Sex and Race and Hispanic Origin — National Health Interview Survey,§ United States, 2021
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

TotalAsian, NH Black or African American, NH Hispanic or LatinoWhite, NH PercentageRace and Hispanic origin
YTHDF2 inhibition potentiates radiotherapy antitumor efficacy
Authors: Liangliang Wang, Xiaoyang Dou, Shijie Chen, Xianbin Yu, Xiaona Huang, Linda Zhang, Yantao Chen, Jiaai Wang, Kaiting Yang, Jason Bugno, Sean Pitroda, Xingchen Ding, Andras Piffko, Wei Si, Chao Chen, Hualiang Jiang, Bing Zhou, Steven J. Chmura, Cheng Luo, Hua Laura Liang, Chuan He, Ralph R. Weichselbaum
Journal: Cancer Cell (2023)
Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques
Authors: Helen L. Wu, Kathleen Busman-Sahay, Whitney C. Weber, Courtney M. Waytashek, Carla D. Boyle, Katherine B. Bateman, Jason S. Reed, Joseph M. Hwang, Christine Shriver-Munsch, Tonya Swanson, Mina Northrup, Kimberly Armantrout, Heidi Price, Mitch Robertson-LeVay, Samantha Uttke, Mithra R. Kumar, Emily J. Fray, Sol Taylor-Brill, Stephen Bondoc, Rebecca Agnor, Stephanie L. Junell, Alfred W. Legasse, Cassandra Moats, Rachele M. Bochart, Joseph Sciurba, Benjamin N. Bimber, Michelle N. Sullivan, Brandy Dozier, Rhonda P. MacAllister, Theodore R. Hobbs, Lauren D. Martin, Angela Panoskaltsis-Mortari, Lois M.A. Colgin, Robert F. Siliciano, Janet D. Siliciano, Jacob D. Estes, Jeremy V. Smedley, Michael K. Axthelm, Gabrielle Meyers, Richard T. Maziarz, Benjamin J. Burwitz, Jeffrey J. Stanton, Jonah B. Sacha
Journal: Immunity (2023)
Estimates of Bivalent mRNA Vaccine Durability in Preventing COVID-19–Associated Hospitalization and Critical Illness Among Adults with and Without Immunocompromising Conditions — VISION Network, September 2022–April 2023
Authors: Ruth Link-Gelles, Zachary A. Weber, Sarah E. Reese, Amanda B. Payne, Manjusha Gaglani, Katherine Adams, Anupam B. Kharbanda, Karthik Natarajan, Malini B. DeSilva, Kristin Dascomb, Stephanie A. Irving, Nicola P. Klein, Shaun J. Grannis, Toan C. Ong, Peter J. Embi, Margaret M. Dunne, Monica Dickerson, Charlene McEvoy, Julie Arndorfer, Allison L. Naleway, Kristin Goddard, Brian E. Dixon, Eric P. Griggs, John Hansen, Nimish Valvi, Morgan Najdowski, Julius Timbol, Colin Rogerson, Bruce Fireman, William F. Fadel, Palak Patel, Caitlin S. Ray, Ryan Wiegand, Sarah Ball, Mark W. Tenforde
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

On September 1, 2022, CDC's Advisory Committee on Immunization Practices (ACIP) recommended a single bivalent mRNA COVID-19 booster dose for persons aged ≥12 years who had completed at least a monovalent primary series. Early vaccine effectiveness (VE) estimates among adults aged ≥18 years showed receipt of a bivalent booster dose provided additional protection against COVID-19-associated emergency department and urgent care visits and hospitalizations compared with that in persons who had received only monovalent vaccine doses (1); however, insufficient time had elapsed since bivalent vaccine authorization to assess the durability of this protection. The VISION Network* assessed VE against COVID-19-associated hospitalizations by time since bivalent vaccine receipt during September 13, 2022-April 21, 2023, among adults aged ≥18 years with and without immunocompromising conditions. During the first 7-59 days after vaccination, compared with no vaccination, VE for receipt of a bivalent vaccine dose among adults aged ≥18 years was 62% (95% CI = 57%-67%) among adults without immunocompromising conditions and 28% (95% CI = 10%-42%) among adults with immunocompromising conditions. Among adults without immunocompromising conditions, VE declined to 24% (95% CI = 12%-33%) among those aged ≥18 years by 120-179 days after vaccination. VE was generally lower for adults with immunocompromising conditions. A bivalent booster dose provided the highest protection, and protection was sustained through at least 179 days against critical outcomes, including intensive care unit (ICU) admission or in-hospital death. These data support updated recommendations allowing additional optional bivalent COVID-19 vaccine doses for certain high-risk populations. All eligible persons should stay up to date with recommended COVID-19 vaccines.